Plasma purification membrane and plasma purification system

ABSTRACT

A plasma purification membrane and a plasma purification system for treating diseases. The above plasma purification membrane is a hollow fiber plasma purification membrane being made of a hydrophobic polymer and a hydrophilic polymer and having a sponge-like structure wherein the pore size is continuously decreased from the outer surface of the membrane toward the inner surface thereof, characterized in that the break strength of the membrane is 50 kgf/cm 2  or more and, in the case of the inner pressure filtration of bovine plasma, the total protein permeability is 50% or more while the immunoglobulin (IgM) permeability is 90% or less.

TECHNICAL FIELD

The present invention relates to a plasma purification membrane forplasma purification using inside-out filtration which is rarely cloggedand has high strength, and a method for producing the same. The presentinvention also relates to a plasma purification system and a method fortreating diseases using the plasma purification membrane.

BACKGROUND ART

A hollow fiber membrane has been widely used for industrial applicationssuch as microfiltration and ultrafiltration. As to the material used inthe membrane, polyethylene, cellulose acetate, polysulfone,polyvinylidene fluoride, polycarbonate, polyacrylonitrile, or the likehas been used. A conventional hollow fiber membrane formed of such amaterial has been developed mainly aiming at improving filtrationperformance. Therefore, as a conventional hollow fiber membrane exhibitslow breaking stress and elongation at break, the hollow fiber membranebreaks due to a rapid temperature change or a pressure fluctuation whenshifting to backwash.

Various attempts have been made to solve this problem. As suggested bythe invention disclosed in Japanese Patent Application Laid-open No.59-228016, a method wherein the polymer density of the entire hollowfiber membrane is increased by increasing the polymer concentration inthe membrane-forming solution may be generally considered. This methodimproves the strength of the membrane, but decreases the pore size ofthe membrane and considerably decreases the water permeability of themembrane. As a result, a hollow fiber membrane having well-balancedstrength and water permeability has not as yet been obtained.

The pore size of the membrane is generally increased in order to improvewater permeability of the membrane. However, an increase in the poresize generally decreases the fractionation (cutoff) performance and thestrength of the membrane.

As described above, a high-performance hollow fiber membrane havingwell-balanced strength, water permeability, and fractionationperformance has not been obtained by a conventional technology. Forexample, Japanese Patent Application Laid-open No. 04-260424 proposes amethod for producing a membrane having high strength and excellent waterpermeability. However, since the membrane obtained by this method has alarge pore size, the water permeability and fractionation performance isnot well-balanced.

Japanese Patent Application Laid-open No. 02-102722 discloses a hollowfiber microfiltration membrane in which the pore size is continuouslydecreased from the outer surface toward the inside of the membrane, isminimized inside the membrane, is continuously increased again towardthe inner surface, and is open on the inner surface. However, whenfiltering liquid or the like from the side of the hollow section (innersurface side) of a membrane having this structure, filtration cannot bestably performed for a long period of time due to the occurrence ofrapid clogging.

Japanese Patent Application Laid-open No. 58-155865 discloses a hollowfiber membrane having a dense layer on at least one surface side of thehollow fiber membrane and a porous layer inside the hollow fibermembrane. Japanese Patent Application Laid-open No. 58-155865 disclosesa hollow fiber membrane made of a vinyl alcohol polymer, but does notdisclose a membrane material comprising a hydrophobic polymer and ahydrophilic polymer. If the hydrophilic polymer is included in thehydrophobic polymer, the molecular chains of the hydrophobic polymerbecome poorly entangled with each other, whereby a high strength may notbe obtained. Moreover, since the hollow fiber membrane made of a vinylalcohol polymer disclosed in Japanese Patent Application Laid-open No.58-155865 has a structure in which the dense layer is formed on theouter surface of the membrane, filtration cannot be stably performed fora long period of time due to the occurrence of clogging when a liquid orthe like is filtered from the side of the hollow section (inner surfaceside) of the membrane.

The applicant of the present invention has provided a hollow fibermembrane comprising a hydrophobic polymer and a hydrophilic polymer andhaving a sponge structure in which the pore size is continuouslydecreased from the outer surface to the inner surface of the membrane.However, this membrane can be merely used for blood dialysis orultrafiltration which does not substantially cause albumin to passtherethrough, and is not suitable for plasma purification (JapanesePatent Application Laid-open No. 11-309355, Japanese Patent No. 3281364,and Japanese Patent No. 3281363).

As described above, a hollow fiber membrane for plasma purificationwhich is well-balanced, exhibits a desired strength, water permeability,and fractionation performance, and which rarely clogs even whenfiltering liquid from the side of the hollow section (inner surfaceside), has not yet been provided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an electron micrograph of the cross section perpendicular tothe longitudinal direction of a hollow fiber membrane of the presentinvention (magnification: ×1,500).

FIG. 2 is an electron micrograph of the inner surface of a membrane ofthe present invention (magnification: ×10,000).

FIG. 3 is an electron micrograph of the outer surface of a membrane ofthe present invention (magnification: ×10,000).

FIG. 4 is an elevation view of an example of a plasma purificationsystem of the present invention.

DISCLOSURE OF THE INVENTION

An objective of the present invention is to provide a plasmapurification membrane which rarely clogs, has high strength, andexhibits excellent water permeability and fractionation performance inplasma purification using inside-out filtration. Another objective ofthe present invention is to provide a plasma purification system and amethod for treating disease using such a plasma purification membrane.

As described above, a plasma purification membrane which rarely clogsand exhibits excellent protein separation properties when filteringliquid or the like from the side of the hollow section of the membrane(hereinafter may be called “inside-out filtration”) has not yet beenprovided. This is because it is impossible to form a pore with a largepore size (pore size in microfiltration membrane region) which allowsplasma protein to pass therethrough in the inner surface of the membranehaving a gradient structure, in which the pore size is continuouslydecreased from the outer surface to the inner surface of the membrane,while maintaining the strength of the membrane.

The present inventor has conducted extensive studies to achieve theabove objectives while 1) forming a gradient structure in which the poresize is continuously decreased from the outer surface to the innersurface of the membrane in order to prevent clogging, and 2) increasinghydrophilicity of the inner surface of the membrane with which a liquidto be filtered comes into contact so that protein or the like does notundergo hydrophobic adsorption. As a result, the present inventor hasfound that a desired membrane can be obtained by using a specificproduction method. This finding has led to the completion of the presentinvention.

The above and other objectives, features, and advantages of the presentinvention will become apparent from the following detailed descriptionand the appended claims.

According to the present invention, a plasma purification membrane whichrarely clogs, has high strength, and exhibits excellent waterpermeability and fractionation performance in plasma purification usinginside-out filtration can be provided.

The basic features and preferred embodiments of the present inventionare given below in order to facilitate better understanding of thepresent invention.

(1) A hollow fiber plasma purification membrane, comprising ahydrophobic polymer and a hydrophilic polymer, having a sponge structurein which a pore size is continuously decreased from an outer surface toan inner surface of the membrane, and having a breaking stress of 50kgf/cm² or more, and a total protein permeability of 50% or more and animmunoglobulin (IgM) permeability of 90% or less when subjecting bovineplasma to inside-out filtration.

(2) The hollow fiber plasma purification membrane according to (1)above, the membrane has circular or elliptical pores having an averagepore size of 1 μm or more on the outer surface of the membrane.

(3) The hollow fiber plasma purification membrane according to (1) or(2), wherein porosity of the outer surface of the membrane is 10% ormore.

(4) The hollow fiber plasma purification membrane according to any oneof (1) to (3), wherein the membrane has a ratio of thickness to internaldiameter of 0.15 to 0.4.

(5) The hollow fiber plasma purification membrane according to any oneof (1) to (4), wherein the membrane has an external diameter of 400 μmor less.

(6) The hollow fiber plasma purification membrane according to any oneof (1) to (5), wherein the membrane comprises an aromatic polysulfoneand polyvinylpyrrolidone, and a polyvinylpyrrolidone concentration onthe inner surface of the membrane is 20 to 45 wt %.

(7) The hollow fiber plasma purification membrane according to (6),wherein the polyvinylpyrrolidone has a weight average molecular weightof 900,000 or more.

(8) The hollow fiber plasma purification membrane according to any oneof (1) to (7), wherein the membrane comprises water-insolublepolyvinylpyrrolidone.

(9) The hollow fiber plasma purification membrane according to any oneof (1) to (8), wherein the membrane is used to treat a patient sufferingfrom age-related macular degeneration.

(10) The hollow fiber plasma purification membrane according to any oneof (1) to (8), wherein the membrane is used to treat a patient sufferingfrom hyperlipidemia.

(11) A method for producing a hollow fiber plasma purification membranecomprising a hydrophobic polymer and a hydrophilic polymer, having asponge structure in which a pore size is continuously decreased from anouter surface to an inner surface of the membrane, and having a breakingstress of 50 kgf/cm² or more, and a total protein permeability of 50% ormore and an immunoglobulin (IgM) permeability of 90% or less whensubjecting bovine plasma to inside-out filtration, comprising the stepsof: discharging a membrane-forming solution and an internal solutionfrom a double annular nozzle, passing the discharged mixture through anair gap, and coagulating the resulting mixture in a coagulation bath;

the method further characterized in that:

a) the membrane-forming solution comprises a hydrophobic polymer, asolvent for the hydrophobic polymer, and a hydrophilic polymer, and hasa ratio of the hydrophilic polymer to the hydrophobic polymer of 27 to60 wt %;

b) the internal solution comprises water and at least one solvent, andhas a water content of 40 to 55 wt %;

c) the membrane-forming solution has a temperature of 50° C. or more atthe nozzle;

d) the coagulation bath has a temperature of 90 to 100° C.; and

e) a ratio of the air gap to a spinning speed is 0.01 to 0.1 m/(m/min).

(12) The method for producing a hollow fiber plasma purificationmembrane according to (11), further comprising the step of applyingradiation to the membrane.

(13) The method for producing a hollow fiber plasma purificationmembrane according to (11) or (12), wherein the hydrophobic polymer is apolysulfone polymer.

(14) The method for producing a hollow fiber plasma purificationmembrane according to any one of (11) to (13), wherein the solvent forthe hydrophobic polymer is N-methyl-2-pyrrolidone.

(15) The method for producing a hollow fiber plasma purificationmembrane according to any one of (11) to (14), wherein the spinningspeed is 60 m/min or more.

(16) A plasma purification system, comprising a plasma separatorincluding a separation membrane which separates blood into blood cellcomponents and plasma components; a plasma component separator includinga separation membrane which separates the separated plasmacomponents-into pathogenic substances and plasma components from whichthe pathogenic substances are removed or reduced; first mixing means formixing the plasma components from which the pathogenic substances areremoved or reduced with a replenishment solution; and second mixingmeans for further mixing the plasma components subjected to the firstmixing means with the blood cell components separated by the plasmaseparator; wherein the separation membrane included in the plasmacomponent separator is the membrane according to any one of (1) to (10).

(17) The plasma purification system according to (16), furthercomprising means for heating plasma upstream of the second mixing meansfor mixing the plasma components with the blood cell components.

(18) The plasma purification system according to (16) or (17),comprising means for heating or cooling plasma downstream of the plasmaseparator and upstream of the plasma component separator.

(19) The plasma purification system according to any one of (16) to(18), wherein an amount of discharge liquid including the pathogenicsubstances discharged from the plasma component separator is equal to anamount of the replenishment solution.

(20) The plasma purification system according to any one of (16) to(19), which is controlled so that an amount of the plasma supplied fromthe plasma separator to the plasma component separator is equal to anamount of the plasma returned to the second mixing means.

(21) The plasma purification system according to any one of (16) to(20), further comprising means for detecting bubbles in the blooddownstream of the second mixing means and upstream of a blood outlet.

(22) A plasma purification method, comprising using the plasmapurification system according to any one of (16) to (21).

(23) A method for treating disease, comprising treating blood of aliving body using the plasma purification system according to any one of(16) to (21).

(24) A method for treating a patient suffering from age-related maculardegeneration, comprising using the plasma purification system accordingto any one of (16) to (21).

(25) A method for treating a patient suffering from hyperlipidemia,comprising using the plasma purification system according to any one of(16) to (21).

The configuration of the hollow fiber blood purification membrane(hereinafter may be simply called “membrane” or “hollow fiber membrane”)of the present invention is described below.

In the present invention, plasma purification means separatingcomponents in plasma. For example, plasma purification means causinguseful proteins in plasma such as albumin and γ-globulin to permeate,and removing unnecessary proteins and lipids. However, since the removaltarget components, the fractionation (cutoff) molecular weight, and thelike differ depending on the type of disease, the plasma purification inthe present invention broadly includes separating the components inplasma.

The hollow fiber membrane of the present invention has a structure inwhich the membrane is integrally and continuously formed from onesurface to the other surface, such as from the inner surface to theouter surface of the membrane. The inside of the membrane from onesurface to the other surface of the membrane has a mesh structure havinga mesh (pore) size of 10 μm or less, and does not include a polymerdeficiency (large pore or void) with a pore size of more than 10 μm. Inthe present invention, this structure is referred to as a spongestructure.

The pore of the mesh structure inside the membrane has a gradientstructure in which the pore size is continuously decreased from theouter surface to the inner surface (or inner surface region) of themembrane in the cross section perpendicular to the longitudinaldirection of the membrane. Specifically, assuming some cylindricalsurfaces are concentric to the center axis extending in the longitudinaldirection of the hollow fiber membrane, the average pore size of thepores in each cylindrical surface is continuously decreased from theouter surface to the inner surface (or inner surface region) of themembrane. This structure is indispensable for ensuring sharpfractionation performance (excellent protein separation properties) whensubjecting plasma to inside-out filtration.

A typical example of the membrane of the present invention is describedbelow in more detail with reference to the drawings.

FIG. 1 is an electron micrograph of a cross section (part) perpendicularto the longitudinal direction of the hollow fiber membrane. FIG. 2 is anelectron micrograph showing the state of the inner surface of themembrane, and FIG. 3 is an electron micrograph showing the state of theouter surface of the membrane.

As shown in FIG. 1, the membrane has a gradient structure in which theaverage pore size is gradually and continuously decreased to the innersurface of the membrane, that is, a mesh structure having a pore sizeanisotropy. The inner surface of the membrane has a dense structure.However, the membrane of the present invention does not have a definiteskin layer as known in the prior art. FIG. 2 shows the state of thedense inner surface. On the other hand, circular or elliptical pores areobserved on the outer surface as shown in FIG. 3.

It is preferable that the pore openings on the inner surface of themembrane be circular, elliptical, mesh, or slit-shaped. It is preferablethat the pore openings on the outer surface be circular or elliptical.

The average pore size of the pores opening on the outer surface of themembrane is 1 μm or more, and preferably 2 μm or more, but 30 μm orless. If the pore size is less than 1 μm, a molding failure mayunpreferably occur due to adhesion between membranes.

The porosity of the outer surface is also important in order to preventadhesion between membranes. The porosity used in the present inventionmay be determined by image-analyzing an electron micrograph of the outersurface of the dried membrane, and converting the image-analyzed resultsinto numerical values. The porosity used in the present invention isdefined as the percentage of the sum of the pore areas in the poroussection with respect to the area of the photographed image, and isrepresented by the following equation (1). Pores having a size of 10pixels or less were excluded from the calculation as noise.Porosity (%)=(sum of pore areas in porous section/area of photographedimage)×100  (1)

The porosity considerably affects adhesion between membranes. If theporosity is small, adhesion occurs due to an increase in the contactarea between adjacent membranes. In worst cases, the entire bundleadheres in the shape of a rod.

Therefore, the porosity must be 10% or more.

However, if the porosity is unnecessarily increased, flexibility of themembrane in the longitudinal direction, that is, the elastic strength isdecreased, whereby a considerable molding failure frequently occursduring molding due to membrane flow and movement at the adhesion part.Therefore, it is preferable that the porosity must be 60% or less inorder not to impair the elastic strength.

The shape, size, and the like of the pores opening on the surface of themembrane may be observed and measured by using an electron microscope.

An average pore size D of the pores opening on the inner surface or theouter surface is a value represented by the following equation (2).D=[{(D _(i) ²)²+ . . . +(D _(n) ²)² }/{D _(i) ² + . . . D _(n)²}]^(1/2)  (2)

In the equation (2), D indicates the average pore size, Di indicates themeasured diameter of the i-th pore, and Dn indicates the measureddiameter of the n-th pore. The measured diameter Di or Dn is indicatedby the diameter of the pore when the pore is almost circular, and isindicated by the diameter of the circle having the same area as the areaof the pore when the pore is not circular.

The membrane of the present invention has a total protein permeabilityof 50% or more, and preferably 80% or more when subjecting bovine plasmato inside-out filtration. If the total protein permeability is less than50%, since considerable amounts of albumin (Alb) and γ-globulin (IgG)(molecular weight: about 160,000) which are very needed by the humanbody are lost, it becomes difficult to use the membrane for treating apatient whose physical strength has decreased.

The membrane of the present invention has a permeability ofimmunoglobulin (IgM) (molecular weight: about 950,000) of 90% or lesswhen subjecting bovine plasma to inside-out filtration. While albuminand γ-globulin are proteins very needed by the human body, it isnecessary to remove high-molecular-weight proteins, such asimmunoglobulin, or lipids depending on the type of disease. If thepermeability exceeds 90%, the membrane may not be effective againstdiseases such as hyperlipidemia.

The membrane of the present invention has a breaking stress of 50kgf/cm² or more, and preferably 60 kgf/cm² or more, even though themembrane has a gradient structure, in which the pore size iscontinuously decreased from the outer surface to the inner surface ofthe membrane, and includes a pore with a large pore size which allowsplasma protein to pass through the inner surface of the membrane. If thebreaking stress of the membrane is less than 50 kgf/cm², a considerableleakage or the like occurs. The breaking stress used in the presentinvention may be determined by dividing the breaking load (kgf) appliedto one hollow fiber membrane by the cross-sectional area (cm²) of themembrane before applying a load.

The hollow fiber membrane of the present invention includes ahydrophobic polymer and a hydrophilic polymer.

As examples of the hydrophobic polymer, a polysulfone polymer, apolyethylene polymer, a polypropylene polymer, a polyvinylidene fluoridepolymer, and the like can be given. The polysulfone polymer and thepolyvinylidene fluoride polymer are preferable from the viewpoint offorming the membrane using a wet process. Of these, the aromaticpolysulfone is most preferably used, since the aromatic polysulfone hasheat stability, acid resistance, and alkali resistance, and improvesblood compatibility by adding the hydrophilic polymer to themembrane-forming solution and forming a membrane using the resultingsolution. As the aromatic polysulfone, a bisphenol A polysulfone isparticularly preferably used.

The hydrophilic polymer is not particularly limited insofar as thepolymer may swell in water but is not dissolved in water. As examples ofsuch a polymer, polymers including a substituent such as a sulfonic acidgroup, a carboxyl group, a carbonyl group, an amino group, an amidegroup, a cyano group, a hydroxyl group, a methoxy group, a phosphoricacid group, a polyoxyethylene group in which the number of repeatingunits is about 1 to 40, an imino group, an imide group, an imino ethergroup, a pyridine group, a pyrrolidone group, an imidazole group, and aquaternary ammonium group, either individually or in combination of twoor more, can be given.

In order to form a membrane using a wet process, a polymer which ismiscible with a solvent and is not miscible with the hydrophobic polymermay be used as the hydrophilic polymer. When the hydrophobic polymerwhich constitutes the hollow fiber membrane is an aromatic polysulfone,polyvinylpyrrolidone is most preferable as the hydrophilic polymer.

As described above, it is most preferable that the membrane of thepresent invention comprises the aromatic polysulfone andpolyvinylpyrrolidone. Since the plasma purification membrane of thepresent invention is used for inside-out filtration, it is preferablethat the concentration of polyvinylpyrrolidone on the inner surface ofthe membrane with which plasma comes into contact be 20 to 45 wt %. Theplasma protein easily undergoes hydrophobic adsorption. Therefore, theimportant factor for preventing clogging during inside-out filtration isthe hydrophilicity of the inner surface of the membrane with which theplasma comes into contact. In the polysulfone membrane includingpolyvinylpyrrolidone (hereinafter may be abbreviated as “PVP”), thePVP-concentration on the inner surface of the membrane is important. Ifthe PVP concentration on the inner surface of the membrane is too low,the inner surface of the membrane exhibits hydrophobicity, whereby theplasma protein is easily absorbed on the inner surface of the membrane.If the PVP concentration on the inner surface of the membrane is toohigh, the amount of PVP eluted into the plasma is increased, andundesirable results may result. Therefore, the PVP concentration whensubjecting plasma to inside-out filtration is 20 to 45 wt %, andpreferably 25 to 40 wt %.

As the polysulfone polymer used in the present invention, a polymerincluding a repeating unit represented by the following formula (3) or(4) can be given. In the formula, Ar represents a di-substituted (paraposition) phenyl group, and the degree of polymerization and themolecular weight are not particularly limited.—O—Ar—C(CH₃)₂—Ar—O—SO₂—Ar—  (3)—O—Ar—SO₂—Ar—  (4)

Since polyvinylpyrrolidone having a higher molecular weight exerts ahigher hydrophilic effect on the membrane, a sufficient effect can beobtained with a smaller amount of addition. Therefore,polyvinylpyrrolidone having a weight average molecular weight of 900,000or more is used in the present invention. In order to provide thehydrophilic effect to the membrane using polyvinylpyrrolidone having aweight average molecular weight of less than 900,000, a large amount ofpolyvinylpyrrolidone must be allowed to remain in the membrane. Thiscauses the amount of substance eluted from the membrane to be increased.If the amount of polyvinylpyrrolidone having a weight average molecularweight of less than 900,000 remaining in the membrane is decreased inorder to decrease the amount of substance eluted from the membrane, thehydrophilic effect becomes insufficient. If polyvinylpyrrolidone havinga weight average molecular weight of 900,000 or more is not used,hydrophilicity becomes insufficient in the thick section of themembrane, whereby plasma protein which has passed through the innersurface region of the membrane adheres in the thick section. As aresult, excellent separation properties cannot be obtained.

The PVP concentration on the inner surface of the membrane is determinedby X-ray photoelectron spectroscopy (XPS). Specifically, the innersurface of the membrane is subjected to XPS measurement by placing aspecimen on a double-sided tape, cutting the specimen in the fiber axialdirection using a cutter, spreading the cut specimen so that the insideof the membrane is the upper side, and measuring the PVP concentrationusing a conventional method. Specifically, the PVP concentration usedherein refers to the concentration determined from the surface nitrogenconcentration (nitrogen atom concentration) and the surface sulfurconcentration (sulfur atom concentration) obtained from the areaintensity of C1s, O1s, N1s, and S2p spectra using the relativesensitivity coefficient peculiar to the measurement device. When thepolysulfone polymer has a structure shown by the formula (3), the PVPconcentration may be calculated using the following equation (5).PVP concentration (wt %)=C ₁ M ₁×100/(C ₁ M ₁ +C ₂ M ₂)  (5)Where,

-   C₁: nitrogen atom concentration (%)-   C₂: sulfur atom concentration (%)-   M₁: molecular weight of PVP repeating unit (111)-   M₂: molecular weight of polysulfone polymer repeating unit (442)

The membrane of the present invention includes water-insoluble PVP. Ifthe entire PVP in the membrane is water-soluble, the amount of substanceeluted from the membrane is unpreferably increased. If the entire PVP iswater-insoluble, excellent protein separation performance is notobtained since the inner surface (or inner surface region) of themembrane exhibits poor swelling properties during plasma filtration. Themembrane of the present invention exhibits excellent membraneperformance since the membrane includes water-insoluble PVP in anappropriate amount.

A method for producing the hollow fiber membrane of the presentinvention is described below.

The hollow fiber membrane of the present invention may be produced byusing a method for producing a hollow fiber membrane, comprising thesteps of: discharging a membrane-forming solution and an internalsolution from a double annular nozzle, passing the discharged mixturethrough an air gap, and coagulating the resulting mixture in acoagulation bath; the method characterized in that:

a) the membrane-forming solution comprises a hydrophobic polymer, asolvent for the hydrophobic polymer, and a hydrophilic polymer, and hasa ratio of hydrophilic polymer to hydrophobic polymer of 27 to 60 wt %;

b) the internal solution comprises water and at least one solvent, andhas a water content of 40 to 55 wt %;

c) the membrane-forming solution has a temperature of 50° C. or more atthe nozzle;

d) the coagulation bath has a temperature of 90 to 100° C.; and

e) a ratio of the air gap to spinning speed is 0.01 to 0.1 m/(m/min).

The hollow fiber membrane of the present invention is produced bydischarging a membrane-forming solution which essentially consists of ahydrophobic polymer, a solvent for the hydrophobic polymer, and ahydrophilic polymer, from a double annular nozzle together with aninternal solution comprising an aqueous solution of a good solvent forthe polymer at a specific concentration, causing the discharged mixtureto pass through an air gap, and causing the resulting mixture tocoagulate in a coagulation bath.

As to the solvent for the polymer, N-methyl-2-pyrrolidone,N,N-dimethylformamide, N,N-dimethylacetamide, and the like can be used.When the hydrophobic polymer is the polysulfone polymer,N-methyl-2-pyrrolidone (hereinafter may be abbreviated as “NMP”) ispreferable. NMP is a solvent having the highest dissolution capabilityfor the polysulfone polymer. For example, NMP has a dissolutioncapability about 1.5 times that of N,N-dimethylacetamide, which isanother good solvent, at room temperature. In a gradient structure inwhich the pore size is continuously decreased from the outer surface tothe inner surface of the membrane, in order to form a pore with a largepore size which allows plasma protein to pass therethrough in the innersurface of the membrane, it is necessary to increase the period of timefrom the beginning of liquid-liquid phase separation induced by thenon-solvent in the internal solution to the completion of the phaseseparation (coagulation) (particle growth time). The polysulfone polymerallows the particle growth time to be increased by using NMP having anextremely high dissolution capability in comparison with the case ofusing another solvent. Since NMP is the best solvent for the polysulfonepolymer, the molecular chains of the polysulfone polymer in the membraneforming solution are well entangled, whereby a membrane having highstrength can be obtained. Therefore, when using the polysulfone polymeras the hydrophobic polymer, the membrane of the present invention isscarcely obtained by using a solvent other than NMP.

The membrane-forming solution essentially consists of the hydrophobicpolymer, a specific hydrophilic polymer such as polyvinylpyrrolidone,and a specific solvent such as N-methyl-2-pyrrolidone. If otheradditives, for example, water, a metal salt and the like known in theart as conventional additives, are added to the membrane-formingsolution, it is difficult to obtain the membrane of the presentinvention.

The hydrophobic polymer concentration in the membrane-forming solutionused in the present invention is not particularly limited insofar as amembrane can be produced from the membrane-forming solution and theresulting membrane has required membrane properties. Thehydrophobic-polymer concentration is 10 to 35 wt %, and preferably 10 to30 wt %. In order to achieve high water permeability and highfractionation (cutoff) molecular weight, the polymer concentration ispreferably as low as 10 to 25 wt %.

The amount of hydrophilic polymer in the membrane-forming solution isalso important. The mixing ratio of the hydrophilic polymer to thehydrophobic polymer is 27 to 60 wt %, and preferably 30 to 60 wt %. Ifthe mixing ratio of the hydrophilic polymer to the hydrophobic polymeris less than 27 wt %, protein permeability may be decreased whensubjecting bovine plasma to inside-out filtration. If the mixing ratioexceeds 60 wt %, the viscosity of the membrane-forming solution isincreased, whereby spinnability tends to become poor during membraneformation.

The temperature of the membrane-forming solution is important, and is50° C. or more, and preferably 60 to 100° C. when discharging thesolution from the nozzle. If the temperature is less than 50° C.,spinnability tends to become poor during membrane formation.

The internal solution is used for forming the hollow section of thehollow fiber membrane, and comprises water and at least one good solventfor the hydrophobic polymer. The water content is preferably 40 to 55 wt%. If the water content is less than 40 wt %, spinnability is poorduring membrane formation. If the water content exceeds 55 wt %, theprotein permeability may be decreased when subjecting bovine plasma toinside-out filtration. The air gap means the distance between the nozzleand the coagulation bath. The ratio of the air gap (m) to the spinningspeed (m/min) is very important in order to obtain the membrane of thepresent invention. This is because the membrane structure of the presentinvention can be obtained on the condition that phase separation fromthe inner surface region to the outer surface region of themembrane-forming solution is induced due to the contact of themembrane-forming solution with the non-solvent component in the internalsolution, and that the phase separation from the inner surface region tothe outer surface region of the membrane has been completed before themembrane-forming solution enters into the coagulation bath.

The ratio of the air gap to the spinning speed is preferably 0.01 to 0.1m/(m/min), and more preferably 0.01 to 0.05 m/(m/min). If the ratio ofthe air gap to the spinning speed is less than 0.01 m/(m/min), it isdifficult to obtain a membrane having the structure and the performanceof the present invention. If the ratio is more than 0.1 m/(m/min), aconsiderable amount of breaking occurs in the air gap due to hightension applied to the membrane, whereby production-unpreferably becomesdifficult.

The spinning speed used herein means the winding speed when the stretchoperation is not performed during a series of hollow fiber membraneproduction process in which the membrane-forming solution dischargedfrom the nozzle together with the internal solution passes through theair gap and the membrane coagulated in the coagulation bath is wound. Ahollow fiber membrane can be more stably produced by enclosing the airgap with a cylinder or the like and causing gas having a constanttemperature and humidity to flow through the air gap at a specific flowrate.

As to the coagulation bath, a liquid in which the polymer is notdissolved, such as water; alcohols such as methanol and ethanol; ethers;aliphatic hydrocarbons such as n(normal)-hexane and n-heptane; and thelike may be used. Of these, water is preferable. It is possible tocontrol the coagulation speed or the like by adding a solvent in whichthe polymer is dissolved in the coagulation bath in a small amount.

The temperature of the coagulation bath is preferably 90 to 100° C. Ifthe temperature of the coagulation bath is less than 90° C., the proteinpermeability may be decreased when subjecting bovine plasma toinside-out filtration. If the temperature of the coagulation bath is100° C. or more, unpreferably the membrane frequently breaks duringmembrane formation.

In order to obtain the membrane of the present invention, the ratio ofthe thickness to the internal diameter of the membrane after coagulationis 0.15 to 0.4, and preferably 0.2 to 0.3. If the ratio of the thicknessto the internal diameter of the membrane is less than 0.15, the absolutestrength of the membrane tends to be decreased. If the ratio exceeds0.4, a membrane having a gradient structure in which the pore size isdecreased from the outer surface to the inner surface (or inner surfaceregion) of the membrane as in the present invention may not be obtained.This is because, since the ratio of the amount of solvent in themembrane-forming solution to the amount of non-solvent in the internalsolution is large, phase separation from the inner surface region to theouter surface region of the membrane-forming solution cannot becompleted using only the amount of the non-solvent in the internalsolution before immersion in the coagulation bath.

The external diameter of the membrane is 400 μm or less, and preferably300 μm or less. Given that the membrane area (filling amount) in themodule must be reduced as the external diameter of the membrane isincreased, as a result, the treatment performance per unit time isunpreferably decreased. On the other hand, the size of the modulecontainer/vessel must be enlarged in order to maintain the membrane area(filling amount) in the module while increasing the external diameter ofthe membrane, whereby the cost is unpreferably increased. Given that themembrane of the present invention is used for medical applications, itis necessary to avoid providing an expensive and large-scale module inorder to reduce the burden on the patients relating to medical expenses.Therefore, the external diameter of the membrane is preferably 400 μm orless due to the above-described relationship between the performance andcost.

The membrane of the present invention may be dried. The membrane may beor may not be impregnated with a moisture retention agent such asglycerol when drying the membrane.

The amount of elution from the membrane can be reduced since a part ofPVP in the membrane may be water-insoluble by applying radiation such aselectron beams or γ-rays to the membrane. The radiation may be appliedbefore or after assembling the module.

The amount of water-insoluble PVP used in the present inventionindicates the amount of PVP obtained by subtracting the amount ofwater-soluble PVP from the total amount of PVP in the membrane. Thetotal amount of PVP in the membrane may be easily calculated byelemental analysis of nitrogen and sulfur.

The amount of water-soluble PVP may be determined by the followingmethod.

In the case where the hydrophobic polymer is the polysulfone polymer,the membrane is completely dissolved in N-methyl-2-pyrrolidone, andwater is added to the resulting polymer solution to cause thehydrophobic polymer to precipitate completely. The amount ofwater-soluble PVP may be determined by allowing the polymer solution tostand and determining the amount of PVP in the supernatant liquid byliquid chromatography.

An example of the plasma purification system of the present invention isdescribed below with reference to the drawing. In FIG. 4, blood suppliedfrom a blood inlet (1) to a blood circuit (2) is fed to a plasmaseparator (4) under pressure by a blood pump (3). The conditions aresufficiently adjusted before introducing the blood into the system byintroducing a replenishment solution such as a physiological salinesolution into the entire system. Bubbles can be removed from the systemby this condition adjustment.

The plasma separator has a function of separating the blood into theblood cell components and the plasma components. As to the plasmaseparator, commercially available filter membrane separators andcentrifugal separators such as Plasmaflow (manufactured by Asahi MedicalCo., Ltd.), Plasmacure (manufactured by Kuraray Co., Ltd.), Sulflux(manufactured by Kaneka Corporation), and Propylex (made by UbeIndustries, Ltd.) can be used. However, the present invention is notlimited thereto.

The plasma separated by the plasma separator passes through a plasmacircuit (5) by a plasma supply pump (6), and is introduced into a plasmacomponent separator (7).

The plasma is separated into the discharge-liquid including pathogenicsubstances and the plasma components from which the pathogenicsubstances are removed or reduced by the plasma component separator (7)The discharge liquid is discharged from a discharge outlet (10) througha discharge tube (8) by a discharge pump (9).

The plasma from which the pathogenic substances are removed or reducedis supplied to a first mixing means (14) for mixing the plasmacomponents with the replenishment solution. The replenishment solutionis introduced through a replenishment solution inlet (13), and issupplied to the first mixing means (14) through a replenishment solutionintroduction tube (11) by a replenishment solution pump (12). As to thefirst mixing means (14) for mixing the plasma components with thereplenishment solution, a tube connector or the like is used.Introduction of the replenishment solution into the system and dischargeof the discharge liquid from the system may be performed continuously orintermittently. As to the replenishment solution, fresh frozen plasma,an albumin product, a physiological saline solution, or the like isused.

The plasma components supplied to the first mixing means (14) are mixedwith the replenishment solution, and supplied to the second mixing means(15) in order to mix with the blood cell components separated by theplasma separator (4) using a plasma recovery pump (17). As to the secondmixing means for mixing the blood cell components with the plasmacomponents, a venous chamber or the like can be used; Blood into whichthe plasma, from which the pathogenic substances are removed or reduced,and the blood cell components are mixed in the second mixing means, andwhich is made the original blood state is recovered through a bloodoutlet 16).

A disease can be improved by removing the pathogenic substances from theblood by repeating the above-described steps. The blood inlet (1) andthe blood outlet (16) may be directly connected with the living body,whereby a treatment can be continuously performed for a long period oftime.

It is preferable to heat the plasma components upstream of the secondmixing means (15)-using a means for heating plasma (18). If thetemperature of the plasma components is too low, unpreferably the plasmacomponents can not be uniformly mixed with the blood cell components, orthe plasma components may not be directly returned to the living bodyfrom the blood outlet (16). As to the means for heating plasma (18),means for directly or indirectly heating the plasma using a heaterand/or warm water can be exemplified.

Since the removal efficiency of the pathogenic substances separated bythe plasma component separator (7) may change to a large extentdepending on the temperature, the plasma introduced into the plasmacomponent separator may be maintained at a desired temperature using aplasma component heating or cooling means (19). In the case where theplasma component heating or cooling means cannot be disposed upstream ofthe plasma component separator due to the circuit arrangement, it ispossible to heat or cool the plasma component separator directly. As tothe heating/cooling means, means for directly or indirectly contactingcooling water, a cooler, or the like with the plasma component separatorduring cooling, or means for directly or indirectly contacting warmwater, a heater, or the like with the plasma component separator duringheating can be used. The temperature is preferably in the range from 0to 42° C.

In the case of directly returning the blood to the living body from theblood outlet (16), it is necessary to always monitor the blood usingmeans for detecting bubbles in the blood (20) so that bubbles do notenter the blood returned. As to the means for detecting bubbles in theblood, a bubble detector can be used.

In order to cause the concentration (blood cell concentration) of theblood introduced into the system to be equal to the concentration (bloodcell concentration) of the blood returned from the system after removingthe pathogenic substances, it is preferable that the amount of dischargeliquid from the plasma component separator be equal to the amount ofreplenishment solution. In order to cause the amount of discharge liquidto be equal to the amount of replenishment solution, the discharge pump(9) and the replenishment solution pump (12) may be controlled. However,since the balance between the amount of discharge liquid and the amountof replenishment solution may change depending on the change with timein the pressure distribution over the entire system, it is preferable tocontrol the pumps and the like of the entire system using a computer. Inorder to cause the concentration (blood cell concentration) of the bloodintroduced into the system to be equal to the concentration (blood cellconcentration) of the blood returned from the system, each pump and eachmixing means may be controlled so that the amount of plasma suppliedfrom the plasma separator to the plasma component separator is equal tothe amount of plasma returned to the second mixing means.

A tube for blood such as a vinyl chloride tube is used as the bloodcircuit, the plasma circuit, and various inlet and outlet tubes. Avalve, a clamp, or the like may be used in combination with such a tube.

The pathogenic substances in the present invention differ depending onthe type of disease. Therefore, the present invention may be applied to,but not limited to, the following diseases. In the case where thedisease is age-related macular degeneration, pathogenic substances suchas fibrinogen (Fbg) and immunoglobulin (IgM) must be removed from blood(plasma). Similarly, in the case where the disease is multiple myeloma,M protein must be removed as pathogenic substances. In the case wherethe disease is primary macroglobulinemia, γ-globulin (IgG) must beremoved. In the case where the disease is myasthenia gravis, ananti-acetyl receptor antibody must be removed. In the case where thedisease is malignant rheumatoid arthritis, a rheumatoid factor andimmune complex must be removed. In the case where the disease ishyperlipemia, LDL cholesterol must be removed. In the case where thedisease is a severe blood type incompatible with pregnancy, Rh bloodtype incompatible sensitizing antibody must be removed. In the casewhere the disease is Guillain-Barre syndrome, a demyelinating factor andantibody must be removed. In the case where the disease is pemphigus,anti-epidermal cell membrane antibody and IgQ must be removed. In thecase where the disease is bullous pemphigoid, an anti-basement membraneantibody and IgG must be removed. In the case where the disease isarteriosclerosis obliterans, LDL cholesterol must be removed. In thecase where the disease is focal glomerular sclerosis, LDL cholesterol,IgG, and C₃ must be removed. In the case where the disease is allogeneicrenal transplantation, an anti-ABO antibody and lymphocyte antibody mustbe removed. The present invention can be also applicable to viraldiseases. In this case, the pathogenic substances are viruses. Forexample, diseases such as hepatitis B, HIV, and viral leukemia can begiven. However, the present invention is not limited to these viraldiseases.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described below by way of examples. However,the present invention is not limited to the following examples.

The measurement methods are as follows.

A hollow fiber membrane used as the measurement specimen was used in adried state.

(Measurement of Water Permeation Amount)

Pure water (25° C.) was caused to permeate from the inner surface to theouter surface of a fiber bundle (mini module in which the number ofmembranes was adjusted so that the inner surface area was 110±10 cm²)with an effective length of 180 mm of which both ends were secured usingan adhesive, and the amount of pure water permeated was indicated inunit of mL/(m²·hr·mmHg).

The effective membrane area was converted to the inner surface area.

(Measurement of Breaking Stress)

The membrane stress was measured under the condition of a specimenlength of 20 mm and a tensile speed of 300 mm/min using an autographAGS-5D manufactured by Shimadzu Corporation.

(Bovine Plasma Evaluation)

Bovine plasma (37° C.) was supplied at 0.5 mL/min to one end of thehollow section (inner surface side) of a fiber bundle (mini module) withan effective length of 180 mm of which both ends were secured using anadhesive, and was discharged from the other end of the hollow section at0.1 mL/min. This cross-flow filtration of one-pass operation wasperformed for 180 min. The membrane area of the fiber bundle wasadjusted by adjusting the number of membranes so that the linearvelocity was 1 cm/min for the amount of bovine plasma supplied at 0.5mL/min. The entire filtrate obtained by 180 min of filtration washomogeneously stirred. The membrane performance was evaluated bydetermining the concentration of each protein in the solution and theplasma before filtration. The permeability is a value represented by thefollowing equation (6).Permeability (%)=(concentration in filtrate)/(concentration in originalsolution)×100  (6)(Measurement of Total Amount of Protein)

The total amount (concentration) of protein in the plasma (originalsolution) or the filtrate from the membrane was measured at a wavelengthof 540 nm using a spectrophotometer after mixing 5 mL of a total proteincoloring reagent (manufactured by Wako Pure Chemical Industries, Ltd.)with 0.1 mL of the solution (plasma (original solution) or filtrate fromthe membrane) and allowing the mixture to stand for 30 min.

(Measurement of Immunoglobulin (IgM) Concentration)

The concentration of immunoglobulin (IgM) in the plasma (originalsolution) or the filtrate from the membrane was measured using a BehringNephelometer Analyzer BM (manufactured by Dade Behring Inc.).

EXAMPLE 1

(Membrane Formation and Removal of Residual Solvent)

20.0 wt % of polysulfone (“P-1700” manufactured by Amoco EngineeringPolymers of the U.S.) and 6.0 wt % of polyvinylpyrrolidone (“K90”manufactured by BASF of Germany, weight average molecular weight:1,200,000) were dissolved in 74.0 wt % of N-methyl-2-pyrrolidone toobtain a homogenous solution. The mixing ratio of polyvinylpyrrolidoneto polysulfone in the membrane-forming solution was 30.0 wt %. Themembrane-forming solution was maintained at 60° C., and discharged froma spinning nozzle (double annular nozzle, 0.1 mm-0.2 mm-0.3 mm, nozzletemperature: 60° C., temperature of membrane-forming solution at nozzle:60° C.) together with an internal solution consisting of a mixedsolution of 46 wt % of N-methyl-2-pyrrolidone and 54 wt % of water. Thedischarged mixture was caused to pass through an air gap having a lengthof 0.96 m, and was immersed in a coagulation bath containing water at95±1° C.

The section from the spinning nozzle to the coagulation bath wasenclosed using a cylindrical tube for a seal so that the outside air didnot enter therein. The spinning speed was fixed at 80 m/min. The ratioof the air gap to the spinning speed was 0.012 m/(m/min).

The wound fiber bundle was cut, and was washed for two hours byshowering hot water at 80° C. on the cut surface of the bundle to removethe residual solvent from the membrane. The membrane was dried for sevenhours using hot blast at 87° C. to obtain a dried membrane having awater content of less than 1%. A part of PVP in the membrane wasinsolubilized by applying γ-rays to the dried membrane at 2.5 Mrad.

(Evaluation of Membrane Structure and Membrane Performance)

The resulting membrane was observed using an electron microscope, and itwas found that the membrane had a sponge structure in which the poresize was continuously decreased from the outer surface to the innersurface of the membrane. FIGS. 1 to 3 show electron micrographs of themembrane obtained in this example. The membrane structure, the membraneperformance, and the like are shown in Table 1. The membrane exhibited ahigh breaking stress of 50 kgf/cm² or more, and had a total proteinpermeability of 50% or more when subjecting bovine plasma to inside-outfiltration. The membrane maintained a stable filtration amount for along period of time without occurrence of rapid clogging during theinside-out filtration of bovine plasma.

EXAMPLE 2

The same operation as in Example 1 was performed except for using aninternal solution consisting of a mixed solution of 54 wt % ofN-methyl-2-pyrrolidone and 46 wt % of water (water content: 46 wt %).The resulting membrane was observed using an electron microscope, and itwas found that the membrane had a sponge structure in which the poresize was continuously decreased from the outer surface to the innersurface of the membrane. The membrane structure and the membraneperformance are shown in Table 1. The membrane exhibited a high breakingstress of 50 kgf/cm² or more, and had a total protein permeability of50% or more when subjecting bovine plasma to inside-out filtration. Themembrane maintained a stable filtration amount for a long period of timewithout occurrence of rapid clogging during the inside-out filtration ofbovine plasma.

EXAMPLE 3

The same operation as in Example 1 was performed except for using aninternal solution consisting of a mixed solution of 58 wt % ofN-methyl-2-pyrrolidone and 42 wt % of water (water content: 42 wt %).The resulting membrane was observed using an electron microscope, and itwas found that the membrane had a sponge structure in which the poresize was continuously decreased from the outer surface to the innersurface of the membrane. The membrane structure and the membraneperformance are shown in Table 1. The membrane exhibited a high breakingstress of 50 kgf/cm² or more, and had a total protein permeability of50% or more when subjecting bovine plasma to inside-out filtration. Themembrane maintained a stable filtration amount for a long period of timewithout occurrence of rapid clogging during the inside-out filtration ofbovine plasma.

EXAMPLE 4

The same operation as in Example 1 was performed except for changing theamounts of polyvinylpyrrolidone and N-methyl-2-pyrrolidone in themembrane-forming solution to 10.0 wt % and 70 wt %, respectively. Themixing ratio of polyvinylpyrrolidone to polysulfone in themembrane-forming solution was 50.0 wt %. The resulting membrane wasobserved using an electron microscope, and it was found that themembrane had a sponge structure in which the pore size was continuouslydecreased from the outer surface to the inner surface of the membrane.The membrane structure and the membrane performance are shown inTable 1. The membrane exhibited a high breaking stress of 50 kgf/cm² ormore, and had a total protein permeability of 50% or more whensubjecting bovine plasma to inside-out filtration. The membranemaintained a stable filtration amount for a long period of time withoutoccurrence of rapid clogging during the inside-out filtration of bovineplasma.

EXAMPLE 5

The same operation as in Example 1 was performed except for using themembrane-forming solution having 8.0 wt % of polyvinylpyrrolidone and 70wt % of N-methyl-2-pyrrolidone. The mixing ratio of polyvinylpyrrolidoneto polysulfone in the membrane-forming solution was 40.0 wt %. Theresulting membrane was observed using an electron microscope, and it wasfound that the membrane had a sponge structure in which the pore sizewas continuously decreased from the outer surface to the inner surfaceof the membrane. The membrane structure and the membrane performance areshown in Table 1. The membrane exhibited a high breaking stress of 50kgf/cm² or more, and had a total protein permeability of 50% or morewhen subjecting bovine plasma to inside-out filtration. The membranemaintained a stable filtration amount for a long period of time withoutoccurrence of rapid clogging during the inside-out filtration of bovineplasma.

COMPARATIVE EXAMPLE 1

The same operation as in Example 1 was performed except for using aninternal solution consisting of a mixed solution of 43 wt % ofN-methyl-2-pyrrolidone and 57 wt % of water (water content: 57 wt %).The resulting membrane was observed using an electron microscope, and itwas found that the membrane had a sponge structure in which the poresize was continuously decreased from the outer surface to the innersurface of the membrane. The membrane structure and the membraneperformance are shown in Table 2. The membrane had a total proteinpermeability of less than 50% when subjecting bovine plasma toinside-out filtration.

COMPARATIVE EXAMPLE 2

The same operation as in Example 1 was performed except for using aninternal solution consisting of a mixed solution of 62 wt % ofN-methyl-2-pyrrolidone and 38 wt % of water (water content: 38 wt %).However, a membrane could not be spun due to occurrence of frequentbreaking.

COMPARATIVE EXAMPLE 3

The same operation as in Example 1 was performed except for changing theamounts of polyvinylpyrrolidone and N-methyl-2-pyrrolidone in themembrane-forming solution to 5.0 wt % and 75.0 wt %, respectively. Themixing ratio of polyvinylpyrrolidone to polysulfone in themembrane-forming solution was 25.0 wt %. The resulting membrane wasobserved using an electron microscope, and it was found that themembrane had a sponge structure in which the pore size was continuouslydecreased from the outer surface to the inner surface of the membrane.The membrane structure and the membrane performance are shown in Table2. The membrane had a total protein permeability of less than 50% whensubjecting bovine plasma to inside-out filtration.

COMPARATIVE EXAMPLE 4

20 wt % of polysulfone, 13 wt % of polyvinylpyrrolidone, and 67 wt % ofN-methyl-2-pyrrolidone used in Example 1 were mixed. However, ahomogenous solution could not be obtained.

COMPARATIVE EXAMPLE 5

The same operation as in Example 2 was performed except for changing thetemperature of the membrane-forming solution to 45° C. and the nozzletemperature to 45° C. (temperature of membrane-forming solution atnozzle: 45° C.) However, a membrane could not be spun due to occurrenceof frequent breaking.

COMPARATIVE EXAMPLE 6

The same operation as in Example 1 was performed except for changing thesolvent from N-methyl-2-pyrrolidone to N,N-dimethylacetamide. Theresulting membrane was observed an electron microscope, and it was foundthat the membrane had a sponge structure in which the pore size wascontinuously decreased from the outer surface to the inner surface ofthe membrane. The membrane structure and the membrane performance areshown in Table 2. The membrane had a total protein permeability of lessthan 50% when subjecting bovine plasma to inside-out filtration.

COMPARATIVE EXAMPLE 7

The same operation as in Comparative Example 6 was performed except forusing a mixed solution of 95-wt % of N,N-dimethylacetamide and 5 wt % ofwater as the internal solution. The resulting membrane was observedusing an electron microscope, and it was found that the membrane had asponge structure in which the pore size was continuously decreased fromthe inner surface to the outer surface of the membrane. The membranestructure and the membrane performance are shown in Table 2. Since arapid increase in pressure (clogging) occurred when 35 min had elapsedafter subjecting bovine plasma to inside-out filtration, the evaluationwas terminated.

COMPARATIVE EXAMPLE 8

The bovine plasma evaluation was performed in the same manner asdisclosed in Example 1 except for using a hollow fiber membrane with aninternal diameter of 200 μm and a thickness of 46 μm obtained by usingthe method disclosed in Example 1 of Japanese Patent ApplicationLaid-open No. 58-155865. Since an increase in pressure (clogging)occurred when 120 min had elapsed after subjecting bovine plasma toinside-out filtration, the evaluation was terminated.

TABLE 1 Example 1 2 3 4 5 Internal diameter (μm) 210 216 208 212 194External diameter (μm) 300 308 304 306 278 Thickness (μm) 45 46 48 47 42Ratio of thickness to 0.214 0.213 0.231 0.222 0.216 internal diameterAmount of water permeation 1310 1600 3600 1050 1440 (mL/(m² · hr ·mmHg)) Average pore size on 1.2 1.2 2.0 1.1 1.1 outer surface (μm)Porosity of outer 15.1 15.5 15.3 17.1 16.2 surface (%) Breaking stress75 74 71 77 76 (kgf/cm²) PVP concentration on 36 36 33 35 34 innersurface (wt %) Total protein 64 90 99 57 66 permeability (%)Immunoglobulin (IgM) 23 56 87 18 25 permeability (%) Presence or absenceof Present Present Present Present Present water-insoluble PVP

TABLE 2 Comparative Example 1 3 6 7 Internal diameter (μm) 190 216 216201 External diameter (μm) 272 304 304 291 Thickness (μm) 41 44 44 45Ratio of thickness to 0.216 0.204 0.204 0.224 internal diameter Amountof water permeation 760 410 410 2850 (mL/(m² · hr · mmHg)) Average poresize on 1.1 1.0 1.0 0.03 outer surface (μm) Porosity of outer 14.9 16.016.0 13.2 surface (%) Breaking stress 75 58 58 42 (kgf/cm²) PVPconcentration on 31 34 34 5 inner surface (wt %) Total protein 47 21 21— permeability (%) Immunoglobulin (IgM) 1 0 0 — permeability (%)Presence or absence of Present Present Present Present water-insolublePVP

EXAMPLE 6

11,400 membranes of Example 1 were bundled and secured at both ends to acylindrical housing using a polyurethane resin to form a module with aneffective membrane area of 2 m². The resulting module was used as aplasma component separator. A system similar to the system shown in FIG.4 was formed using Plasmaflow (manufactured by Asahi Medical Co., Ltd.;membrane area: 0.8 m²) as a plasma separator, and human blood wastreated using the system for three hours.

The treatment conditions were as follows.

Amount of blood supplied to plasma separator: 70 mL/min, amount ofplasma component supplied from plasma separator to plasma componentseparator: 20 mL/min, amount of discharge liquid: 5 mL/min, amount ofreplenishment solution supplied: 5 mL/min, temperature of means forheating plasma (18): 37° C., temperature of means for heating or coolingplasma (19): 25° C., and replenishment solution: albumin product.

The blood of a patient suffering from age-related macular degenerationwas used as the objective blood, and the system was directly connectedwith the human body.

The above treatment was performed four times at intervals of 10 days. Asa result, alteration in visual acuity decreased with time ceased afterthe second treatment, and improvement of vision was recognized after thefourth treatment. The values of fibrinogen and immunoglobulin in theblood before the treatment were 320 mg/dL and 120 mg/dL, respectively.These values were clearly reduced to 140 mg/dL and 40 mg/dL respectivelyafter the treatment.

EXAMPLE 7

The blood of a patient suffering from hyperlipidemia was treated for 200min by using the same method as in Example 6. The treatment conditionswere as follows. Amount of blood supplied to plasma separator: 100mL/min, amount of plasma component supplied from plasma separator toplasma component separator: 40 mL/min, amount of discharge liquid: 5mL/min, amount of replenishment solution supplied: 5 mL/min, temperatureof means for heating plasma (18): 37° C., temperature of means forheating or cooling plasma (19): 20° C., and replenishment solution:albumin preparation. The treatment was performed twice at an interval ofone week. As a result, the total cholesterol value in the blood, whichwas 560 mg/dL before the treatment, was reduced to 190 mg/dL after thetreatment.

INDUSTRIAL APPLICABILITY

According to the present invention, an excellent plasma purificationmembrane which rarely clogs, and has high strength during plasmapurification using inside-out filtration, and an excellent bloodpurification system were obtained. Therefore, the present invention canbe used for drug applications, medical applications, and generalindustrial applications.

1. A hollow fiber plasma purification membrane, comprising: an aromaticpolysulfone and polyvinylpyrrolidone and having a polyvinylpyrrolidoneconcentration on an inner surface of the membrane of 20 to 40 wt%, themembrane having a sponge structure in which a pore size is continuouslydecreased from an outer surface to the inner surface of the membrane,and having a breaking stress of 71 kgf/cm² or more, and when subjectingbovine plasma to inside-out filtration the membrane having a totalprotein permeability of 50% or more and an immunoglobulin (IgM)permeability of 90% or less when subjecting bovine plasma to inside-outfiltration.
 2. The hollow fiber plasma purification membrane accordingto claim 1, wherein the membrane has circular or elliptical pores havingan average pore size of 1 μm or more on the outer surface of themembrane.
 3. The hollow fiber plasma purification membrane according toclaim 1, wherein porosity of the outer surface of the membrane is 10% ormore.
 4. The hollow fiber plasma purification membrane according toclaim 1, wherein the membrane has a ratio of thickness to internaldiameter of 0.15 to 0.4.
 5. The hollow fiber plasma purificationmembrane according to claim 1, wherein the membrane has an externaldiameter of 400 μm or less.
 6. The hollow fiber plasma purificationmembrane according to claim 1, wherein the polyvinylpyrrolidone has aweight average molecular weight of 900,000 or more.
 7. The hollow fiberplasma purification membrane according to claim 1, wherein the membranecomprises water-insoluble polyvinylpyrrolidone.
 8. The hollow fiberplasma purification membrane according to claim 1, wherein the membraneis used to treat a patient suffering from age-related maculardegeneration.
 9. The hollow fiber plasma purification membrane accordingto claim 1, wherein the membrane is used to treat a patient sufferingfrom hyperlipidemia.
 10. A plasma purification system, comprising: aplasma separator including a separation membrane which separates bloodinto blood cell components and plasma components; a plasma componentseparator including a separation membrane which separates the separatedplasma components into pathogenic substances and plasma components fromwhich the pathogenic substances are removed or reduced; first mixingmeans for mixing the plasma components from which the pathogenicsubstances are removed or reduced with a replenishment solution; andsecond mixing means for further mixing the plasma components subjectedto the first mixing means with the blood cell components separated bythe plasma separator; wherein the separation membrane included in theplasma component separator is the membrane according to claim
 1. 11. Theplasma purification system according to claim 10, further comprisingmeans for heating plasma upstream of the second mixing means for mixingthe plasma components with the blood cell components.
 12. The plasmapurification system according to claim 10, comprising means for heatingor cooling plasma downstream of the plasma separator and upstream of theplasma component separator.
 13. The plasma purification system accordingto claim 10, wherein an amount of discharge liquid including thepathogenic substances discharged from the plasma component separator isequal to an amount of the replenishment solution.
 14. The plasmapurification system according to claim 10, which is controlled so thatan amount of the plasma supplied from the plasma separator to the plasmacomponent separator is equal to an amount of the plasma returned to thesecond mixing means.
 15. The plasma purification system according toclaim 10, further comprising means for detecting bubbles in the blooddownstream of the second mixing means and upstream of a blood outlet.16. A plasma purification method comprising using the plasmapurification system of claim 10 for treating blood, the processcomprising the steps of: subjecting the blood with a separation membranewhich separates the blood into cell components and plasma components;subjecting the plasma component with a membrane that separates orreduces pathogenic substances from plasma; mixing the plasma from whichthe pathogenic substances are remove or reduced with a replenishingsolution; and further mixing the mixture of plasma and replenishingsolution with the blood cells components separated by the plasmaseparator.
 17. The method of claim 16, wherein said method treats adecease from blood of a leaving body.
 18. The method of claim 16,wherein the method is used for treating a patient suffering fromage-related macular degeneration.
 19. The method of claim 16, whereinthe method is used for treating a patient suffering from hyperlipidemia.20. A method for producing a hollow fiber plasma purification membranecomprising a hydrophobic polymer and a hydrophilic polymer, having asponge structure in which a pore size is continuously decreased from anouter surface to an inner surface of the membrane, and having a breakingstress of 71 kgf/cm² or more, and a total protein permeability of 50% ormore and an immunoglobulin (IgM) permeability of 90% or less whensubjecting bovine plasma to inside-out filtration, comprising the stepsof: discharging a membrane-forming solution and an internal solutionfrom a double annular nozzle, passing the discharged mixture through anair gap, and coagulating the resulting mixture in a coagulation bath;the method further characterized in that: a) the membrane-formingsolution comprises a hydrophobic polymer, a solvent for the hydrophobicpolymer, and a hydrophilic polymer, and has a ratio of the hydrophilicpolymer to the hydrophobic polymer of 27 to 60 wt %; b) the internalsolution comprises water and at least one solvent, and has a watercontent of 40 to 55 wt%; c) the membrane-forming solution has atemperature of 50° C. or more at the nozzle; d) the coagulation bath hasa temperature of 90 to 100° C.; and e) a ratio of the air gap tospinning speed is 0.01 to 0.1 m/(m/min).
 21. The method for producing ahollow fiber plasma purification membrane according to claim 20, furthercomprising the step of applying radiation to the membrane.
 22. Themethod for producing a hollow fiber plasma purification membraneaccording to claim 20, wherein the hydrophobic polymer is a polysulfonepolymer.
 23. The method for producing a hollow fiber plasma purificationmembrane according to claim 20, wherein the solvent for the hydrophobicpolymer is N-methyl-2-pyrrolidone.
 24. The method for producing a hollowfiber plasma purification membrane according to claim 20, wherein thespinning speed is 60 m/min or more.